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8 Articles in Volume 6, Issue #6
Choosing and Using a Low Level Laser in Pain Management
Clinical Bioethics
Cranial Electrotherapy Stimulation in the Treatment of Fibromyalgia
Fibromyalgia: New Hope and New Pharmaceuticals
Identifica tion and Management of Cardiac -Adrenal-Pain Syndrome
Interventional Therapy
Superior Pharyngeal Constrictor Muscle Pain
Treating Neuropathic Pain in Multiple Sclerosis (MS)

Identifica tion and Management of Cardiac -Adrenal-Pain Syndrome

Severe, chronic, under-treated pain may produce cardiac and adrenal complications, that in some pain patients, can lead to premature death.

Severe pain is well-known to stimulate the cardiac and adrenal systems.1-7 Despite this knowledge, there are few reported systematic investigations of these complications in clinical patients. More importantly, clinical treatment of pain’s complications on the cardiac and adrenal systems has not heretofore been practically addressed.

Those chronic pain patients who demonstrate physiologic complications involving the heart and adrenal glands are obviously those who have a most serious pain problem and who must be managed with the most aggressive measures.6,7 Reported here are two systematic investigations of some cardiac and adrenal complications in severe, chronic pain patients. The results of these efforts clearly show that some patients demonstrate cardiac and adrenal complications that can be easily diagnosed in an outpatient clinical setting and which can usually be controlled or ameliorated by aggressive pain treatment. The most obvious and easily detectable cardiac complications are tachycardia and hypertension. Severe pain causes the adrenal glands to secrete abnormal levels of catecholamines (e.g., adrenalin) and glucocorticoids (e.g., cortisol). Pain’s impact on the adrenal gland is biphasic.2 Severe pain initially causes an outpouring of catecholamines and glucocorticoids in an effort to neutralize pain’s adverse affects (see Figure 1), but the adrenal gland may later exhaust if pain is severe and unremitting.2 At this time, serum testing may demonstrate severe hormonal deficiencies.4 The tachycardia and hypertension observed in severe chronic pain patients is at least partially the result of excess adrenal hormone production, but central nervous system over-stimulation produced by severe pain also contributes to tachycardia and hypertension.6,7 Over-stimulation of the pituitary-adrenal axis and other adrenergic centers in the brain appear to act concordantly. It is pain’s over-stimulation of the nervous system that is the root cause of most cardiac and adrenal complications, and they can be identified by simple clinical screens. Once identified, treatment can be partially guided by on-going monitoring of these complications.

Figure 1. Schematic of the effects of excess pain on the hypothalmus-pituitary-adrenal axis with some of the serious cardiac-adrenal complications shown.

Background

Beginning in the 1960’s, investigators began to report cardiac and adrenal abnormalities in clinical pain patients as well as in experimental studies. Initially these abnormalities were considered biologic tracers or markers rather than serious complications of pain. Shenkin, in 1964, first observed that chronic pain changed the diurnal patterns of plasma cortisol levels.1 Since this report, other observers have recognized cortisol abnormalities in acute and chronic pain patients, including post-operative patients.1-3 Reduced adrenal reserve has been documented in severe, chronic, intractable pain patients.2 Elevated blood pressure and pulse rates have been observed both in clinical patients with acute and chronic pain and under experimental conditions.3,6,7

In 1999, Richard Chapman wrote a seminal article entitled “Suffering: The Contributions of Persistent Pain.”8 Chapman hypothesized that much of the suffering and agony had to be, at least in part, the over-stimulation of the hypothalamus-pituitary-adrenal axis, since severe pain is basically a severe stressor. Indeed Liebeskind wrote that “Pain can kill” and others have also described the immense suffering and medical necessity to treat severe pain.6,9 The motivation for the investigations reported here was to document whether the stress of severe, chronic pain causes a clinical cardiac-adrenal-pain syndrome which can be identified in clinical patients and, if so, whether pain treatment can ameliorate these complications.

Identification of a Cardiac-Adrenal-Pain Syndrome

To initially determine if there is an easily detectable cardiac-adrenal-pain syndrome, 91 consecutive, severe chronic pain patients who were admitted to the author’s outpatient intractable pain treatment clinic in California were evaluated. At the time of referral, they were screened for the following complications:

  1. Blood pressure above 130/90mmHg
  2. Pulse rate over 84 per minute
  3. Early morning serum cortisol above 20 or below 5ug/dl
  4. Erythrocyte sedimentation rate (ESR) above 20mm per hour

ESR was included as a screening tool because excess adrenal hormone secretion and stress are known to cause a variety of immune changes.10,11

All subjects were adults between the ages of 30 and 62 years. Females and males constituted, respectively, 54% and 46% of the group. Their pain duration ranged in length from 1 to 45 years. To be eligible for this study, their pain had to be described as severe, constant, and interfered with sleep, eating, dressing, or other activities of daily living. All patients were referred to the clinic after failing to achieve pain control by a plethora of standard measures including psychotherapy, physical therapy, paraspinal corticoid injections, non-opioid medications, and standard dosages of weak opioids. All patients were taking a weak opioid in the form of hydrocodone, tramadol, propoxyphene, or codeine at the time of referral. Without opioid medication, patients claimed to be incapacitated and confined to home or bed.

Cardiac and/or adrenal complications were readily apparent (see Table 1). Only 7 (7.7%) of patients failed to demonstrate at least one cardiac or adrenal abnormality. The majority demonstrated elevated blood pressure (60, 65.9%) or elevated pulse rate (46, 50.5%). Seventeen (18.7%) had pulse rates over 100 per minute (see Table 1). Forty-seven (47.3%) had either elevated or reduced serum cortisol and 33% showed an elevated sedimentation rate. There was considerable demonstration of multiple abnormalities in a single patient. Fifty-nine (64.5%) had two or more abnormal screening tests. Twenty-five (27.4%) had three abnormal screens and four (4%) demonstrated the presence of all four screens. Results in this initial study clearly indicated that severe, chronic pain that was constant and debilitating produced easily detectable cardiovascular and adrenal complications.

Will Pain Treatment Ameliorate Cardiac-Adrenal

Complications?

Since the pilot screening study showed that cardiac-adrenal complications could be easily detected, a second study was done to determine if pain treatment could eliminate or ameliorate these complications. The working premise was that improvement in cardiac and adrenal complications from adequate pain treatment would provide evidence that severe, chronic pain itself, and not some other condition, was producing the observed cardiac-adrenal abnormalities.

Table 1. Cardiac-Adrenal Abnormalities in 91 Severe, Chronic Pain Patients
Abnormalities # %
Hypertension above 130/90 (mm/Hg) 60 65.9%
Pulse Rate 84 per minute or above 46 50.5%
Elevated Serum Cortisol above 20ug/dl 28 30.8%
Low Serum Cortisol below 5ug/dl 15 16.5%
Erythrocyte Sedimentation Rate (ESR) above 20 (mm/hr) 30 33.0%
Physiologic Abnormalities No. with Abnormality Mean Before Treatment (SD) Mean After Treatment (SD) Statistical Significance
High systolic blood pressure (mm/Hg) 28 152.3 ± 19.5 136.3 ± 19.2 t = 3.51; df = 27; p< 0.01
High diastolic blood pressure (mm/Hg) 28 98.4 ± 16.3 63.1 ± 10.8 t = 5.41; df = 27; p< 0.01
Elevated pulse rate per minute 21
93.1 ± 7.9 63.9 ± 15.0 t = 2.80; df = 20; p< 0.01
Low serum cortisol concentration (ug/dl) 7 3.6 ± 1.0
8.6 ± 1.6 t = 4.02; df = 6; p< 0.01
High serum cortisol (ug/dl) 12 24.5 ± 2.6 16.2 ± 6.5 t = 4.67; df = 11; p< 0.01
Low serum pregnenolone (ng/dl) 18 13.6 ± 3.0 50.1 ± 52.7 t = 3.0; df = 17; p< 0.01
High erythrocyte sedimentation rate (mm/hr) 10 33.9 ± 10.3 10.5 ± 7.4 t = 6.0; df = 9; p< 0.01
Table 2.

Methodology

Fifty, (50) consecutive patients, some of whom were in the first study, were selected for investigation. Criteria and procedures described in the identification study were identical except serum pregnenolone was added as a second screen for adrenal hormone complications. Pregnenolone is the precursor of all glucocorticoids and sex hormones including progesterone, estrogen, and testosterone. Additionally, it enters the serum, crosses the blood-brain barrier, and acts as a hormone by attaching to receptors in nervous tissue.

Complications of Excess and Deficient Cortisol
Pregnenolone Serum Levels
Excess
Deficient
Decalcification of bone and teeth (osteoporosis)
Anorexia
Hyperglycemia (diabetes)
Muscle wasting weakness, depression
Hypertension
Fatigue
Truncal obesity
Poor pain control
Muscle wasting
Memory-attention deficit
Immune abnormalities
Loss of libido, Weight loss
Note: “Excess” is similar to Cushing’s Disease and “Deficient” is similar to Addison’s Disease
Table 3.

After screening in the first week of treatment, repeat assessment of these same abnormalities was done after 90 or more days of adequate pain treatment. All patients had severe pain over a period ranging from 3 to 22 years and all had failed multiple, non-opioid pain treatments. There were 18 (36%) males and 32 (64%) females and the patients’ ages ranged from 36 to 68 years. At the time of referral, patients were all being treated with 4-8 daily dosages of hydrocodone or codeine-acetaminophen compounds with a daily morphine equivalency estimated in the range of 20 to 40mg. There was a high prevalence of physiologic abnormalities detected in these patients. Highest prevalence was hypertension (56%) and lowest prevalence was elevated ESR (20%). Forty-eight of the 50 (96%) patients demonstrated at least one physiologic abnormality (see Table 2).

Figure 2. Blood Pressure and Pulse at-home patient monitoring to be completed by patient and family.

After the initial screens were done, treatment was started with a long-acting opioid preparation consisting of methadone, fentanyl transdermal, or a sustained release preparation of oxycodone or morphine. Additionally, patients received one or two short-acting opioids for breakthrough pain. These consisted of fentanyl transmucosal citrate, hydrocodone, oxycodone, morphine, or hydromorphone. Estimated daily morphine treatment equivalency ranged from 400 to 1000mg. Other components of treatment included stretching exercises, participation in patient support groups, topical analgesics, and nutritional supplements. All patients attended an outpatient clinic on a monthly basis at which time daily opioid dosage was titrated upward to maximally suppress pain or, alternately, reduced if sedation was apparent.

Results

Following pain treatment of approximately 90 or more days, physiologic abnormalities normalized in most cases. The percentage reduction of patients who demonstrated a physiologic abnormality before and after 90 days of treatment was statistically significant in all instances. Reductions in the percentage of patients with a physiologic abnormality were as follows: 1) hypertension was reduced from 56% to 28% of the patients; 2) tachycardia was reduced from 42% to 18%; 3) elevated morning cortisol concentration decreased from 24% to 4%; 4) low serum cortisol concentration almost disappeared with treatment (14% to 2%); 5) low serum pregnenolone concentration was reduced from 36% to 6%; and 6) elevated ESR was reduced from 20% to 6% of the patients (see Table 2).

Concordant with these reductions, the mean values of physiologic abnormalities showed a significant trend toward normalization (see Table 2). Mean systolic and diastolic blood pressure, elevated cortisol serum concentration, and elevated ESR were significantly lowered after treatment. Similarly, low mean concentrations for serum cortisol and pregnenolone moved closer to normal at the end of treatment (p<0.01).

Adrenal Complications

The classic descriptions of Addison’s Disease (adrenal insufficiency) and Cushing’s Disease (adrenal excess) are applicable to pain patients. All of the complications of these two diseases of the adrenal gland can be observed in some pain patients depending on the reserve status of their adrenal glands (see Table 3). In the initial phase of adrenal stimulation there is an excess output of adrenal hormones, with the adrenal gland exhausting if pain is not well controlled. One area of poor understanding is the presence of immune serum abnormalities in severe chronic pain patients. In the studies reported here, ESR was assessed. While it is known that abnormal adrenal secretion patterns are associated with immune serum abnormalities, it is not clear why ESR’s would be elevated with uncontrolled pain and normalize d with pain treatment.10,11 This is clearly an area that demands clinical study.

Table 4. Some Potential Sequelae of Chronic Tachycardia
  • Exhaustion — fatigue
  • Insomnia
  • Attention deficit - memory impairment
  • Immobilization
  • Shun social interaction
  • Angina — sudden death in patients with underlying heart disease
  • Possibly, Arteriosclerosis
Table 5. Recommended Clinical Management Of The
Cardiac-Adrenal-Pain Syndrome
  • Identify its presence at the initial pain evaluation by:
  1. Blood pressure
  2. Pulse rate
  3. Early morning serum cortisol and pregnenolone
  • Monitor control of the syndrome by routine pulse and blood pressure screening. Patient can monitor at home. Repeat serum cortisol and pregnenolone levels to insure patient is in normal range.
  • Develop an aggressive treatment plan which may include:
    1. High dose, multiple opioids for baseline and breakthrough pain
    2. Intrathecal opioid administration
    3. Implanted electrical stimulator
  • Frequent clinical visits for close monitoring - usually monthly
  • Use ancillary medications to bring the pulse rate below 84 per minute. May require benzodiazepines, NMDA antagonists, or carisoprodal, in difficult cases.
  • Supplement pregnenolone deficiency up to 200mg a day if necessary to maintain a normal serum range.
  • Cardiac Complications

    Chronic tachycardia is a relatively unstudied clinical problem, since it is usually only seen with such unusual conditions as hyperthyroidism or pheochromocytoma. Some chronic severe pain patients may, however, endure tachycardia for years with some having having pulse rates over 100 per minute. This extraordinary situation undoubtedly precipitates multiple cardiac complications and is likely a factor in the sudden death of some pain patients. Angina, arrhythmia, and congestive heart failure may be present in an ambulatory, severe pain patient and be remarkably controlled when the patient’s painful condition is adequately treated and the pulse rate lowered below 84 per minute. It is obviously a most serious clinical condition with multiple sequelae, and it must be aggressively treated for the welfare of the pain patient (see Table 4). The hallmark of chronic tachycardia, defined here as a pulse rate over 84 per minute, is exhaustion and fatigue. It is also highly associated with insomnia and attention deficit-memory impairment. A striking clinical observation made by the author in patients with high pulse rates is the presence of immobilization and a shunning of social interaction. This, of course, is additive to the patient’s basic cause of pain which may worsen with movement or activity. Fundamentally, the patient seeks the shelter and calm of a chair or couch, and may remain quite immobilized for hours at a time.

    In addition to tachycardia and hypertension there are likely other cardiac complications. Angina, coronary spasm, and arrhythmias are likely consequences in pain flares which produce excess adrenaline output and central adrenergic discharge. Also, some preliminary studies report that painful conditions may produce significant lipid abnormalities that will aggravate cardiac complications.12-13

    Practical Management

    The most critical component of pain management is simple identification and on-going monitoring of the presence of cardiac-adrenal complications. Once identified, ongoing monitoring, particularly of pulse rate and blood pressure, should be done. Control of pulse and blood pressure is an excellent marker for pain treatment effectiveness. At home BP and pulse readings taken by the patient are very useful. In fact, it is probably a far better, and more objective, measure than the standard 1 to 10 pain scale—particularly in chronic patients. Patients can easily obtain an inexpensive apparatus to monitor blood pressure and pulse rate at home. A copy of the at-home monitoring form used by the author is shown (see Figure 2). It is recommended that the pulse rate be maintained below 84 per minute and the blood pressure below 130/90mm Hg.

    If pulse and blood pressure can’t be controlled by conventional means, it may be necessary to use aggressive therapeutic measures including high dose oral opioids, intrathecal therapy, or an implanted electrical stimulator. It may further be necessary to use a benzodiazepine to achieve control. Carisoprodal may be particularly effective, and this may partly explain its great popularity with pain patients. Methadone and propoxyphene, which have N-methyl D-aspartate (NMDA) receptor antagonism activity, have been used by the author to control tachycardia in some resistant cases.

    Adrenal gland function can easily be screened by an early morning serum cortisol and pregnenolone assay. If the results are high, the adrenal gland is showing good reserve and is being over-stimulated by pain. If pregnenolone or cortisol is low, it indicates inadequate hormone production due to exhausted adrenal output. Consequently, better pain control is essential. Once pain control is adequate, cortisol and pregnenolone levels usually normalize, but there are exceptions. Pregnenolone levels appear slightly more difficult to control than cortisol. Persistent low serum levels of pregnenolone suggest that supplementation with oral pregnenolone may be needed with required dosages ranging from 50 to 200mg per day.14,15

    Cardiac symptoms of angina and even heart failure are quite common in the author’s experience with even young severe, chronic pain patients. Co-management with a cardiologist may be required. An endocrinologist may also need to assist with adrenal hormone replacement.

    The key to managing the cardiac-adrenal-pain syndrome is recognition that it exists in some chronic pain patients, and that it must be monitored and controlled by aggressive pain treatment.

    Summary

    Severe chronic pain may produce cardiac and adrenal complications which is referred to herein as “Cardiac-Adrenal-Pain Syndrome.” The presence of this syndrome should clearly signal to the practitioner that the patient’s pain is so severe as to over-stimulate the heart and adrenal glands to produce complications which may produce severe pathology and even death. Although there are sophisticated tests which may more clearly elucidate pain’s impact on the heart and adrenal glands, simple pulse rate, blood pressure, and an early morning assay of cortisol and pregnenolone can provide rapid, clinical identification of the syndrome. If it is present, aggressive measures must be taken to control the pain lest further complications as a result of pain itself, will develop. It may be necessary to use ancillary medications to lower elevated blood pressure or pulse rate in addition to supplementing hormone deficiencies.

    This syndrome may produce complications not yet fully appreciated. There are few clinical conditions that produce chronic tachycardia. This complication may lead to a wide variety of cardiac disorders including angina, athecosclerosis, congestive heart failure, arrhythmias, and sudden death. Abnormal glucocorticoid levels in excess or deficiency are known to produce, among other complications, profound impacts on the immune system and skeletal structure.

    Due to the very serious ramifications of the cardiac-adrenal-pain syndrome, it is highly recommended that physicians test for blood pressure, pulse rate, and cortisol/pregnenolone levels in all chronic, severe pain patients and aggressively treat pain to ameliorate such complications.

    Acknowledgement

    The studies reported here would not have been possible without the outstanding dedication of Laura Herman, RN, NP.

    Last updated on: May 16, 2011
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